The existence of opioid receptors to which opioids such as morphine bind was verified in the early 1970's. At present, opioid receptors are mainly classified into three types, i.e., .mu., .delta. and .kappa.. Morphine mostly acts on the .mu. acceptor as an agonist and exhibits pharmaceutical activities such as analgesic activity, enterokinetic inhibition, and respiratory inhibition.
Since 1975, several endogenous morphine-like substances that bind to the opioid receptors have been successively discovered. All of these substances found to date are peptide compounds and are collectively referred to as opioid peptides. The pharmaceutical activities of the opioid peptides are believed to be basically the same as those of morphine. They are expected to be potentially safer drugs than morphine since they are substances naturally exist in living bodies. However, natural opioid peptides have problems from the pharmacokinetical standpoint, and they have not been used as clinical medicaments.
In the 1980's, Delmorphine that contains D-alanine was isolated from cutises of frogs. It was found that Delmorfine has about 1000-fold higher analgesic effect than morphine at intraventricular administration and is relatively stable in living bodies. Since then, synthetic opioid peptides containing D-amino acids have been prepared. In particular, synthetic opioid peptides with high .kappa. acceptor selectivity are considered as hopeful non-narcotic analgesics and clinical trials have begun. However, the probability of their success as clinical medicaments is doubtful from the viewpoints of efficacy, possible side effects probably due to properties as .kappa. agonists, and commercial practicability.
Furthermore, it is impossible to use these synthesized opioid peptides as orally available medicaments, and accordingly, they can not be substitutive drugs for MS contin, e.g., which is an orally available controlled release preparation comprising morphine sulfate that has been widely used recently as a medicament for treatment of cancerous pain. However, daily dose of MS contin may occasionally be increased up to gram order, which sometimes leads to difficulty in oral administration. In some cases, its administration cannot be continued because of side effects such as pruritus due to its activity on the release of histamine. Therefore, substitutive medicaments are desired which have higher safety and efficacy than morphine.